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Gene Review

SLC6A2  -  solute carrier family 6 (neurotransmitter...

Homo sapiens

Synonyms: NAT1, NET, NET1, Norepinephrine transporter, SLC6A5, ...
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Disease relevance of SLC6A2


Psychiatry related information on SLC6A2


High impact information on SLC6A2

  • SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites [11].
  • Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes [11].
  • METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function [3].
  • Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene [3].
  • The DAT internalization signal is conserved across SLC6 neurotransmitter carriers and is functional in the homologous norepinephrine transporter, suggesting that this region is likely to be the endocytic signal for all SLC6 neurotransmitter transporters [12].

Chemical compound and disease context of SLC6A2


Biological context of SLC6A2

  • We genotyped five genetic variants of SLC6A2, three in the promoter region and two in the intronic sequence, in 1,950 subjects recruited from the Suita study [1].
  • SLC6A2 may be one of the genes that contribute to hypertension in Japanese. To our knowledge, this is the first report to detect associations between SLC6A2 genetic variants and blood pressure [1].
  • No behavioral, cognitive, or brain MRI volume measurement significantly differed across NET1 or DRD1 genotypes at an alpha of 0.01 [17].
  • Substrate binding stoichiometry and kinetics of the norepinephrine transporter [8].
  • To understand the molecular mechanisms regulating human NET (hNET) gene expression, we isolated and characterized an hNET genomic clone encompassing approximately 9 [18].

Anatomical context of SLC6A2

  • Membranes were prepared from rat brains or human embryonic kidney cells expressing the cloned human dopamine (hDAT), serotonin (hSERT), and norepinephrine (hNET) transporters. beta-(4'-(125)Iodophenyl)tropan-2beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding and other assays followed published procedures [19].
  • We verified physical association of NET with PP2A-Ar via co-immunoprecipitation studies using mouse vas deferens extracts and with 14-3-3 via a fusion pull-down approach, implicating specifically the hNET NH2-terminus for interactions [2].
  • The synaptic action of norepinephrine is terminated by NaCl-dependent uptake into presynaptic noradrenergic nerve endings, mediated by the norepinephrine transporter (NET) [18].
  • Expression of hNET-Ex15L exerted a dominant negative effect on plasma membrane expression of the wild-type hNET and thus may represent a novel mechanism for regulation of noradrenergic neurotransmission [20].
  • Using hNET stably transfected HEK-293 and LLC-PK1 cells, as well as transiently transfected COS-7 cells, we demonstrate that PKC-activating phorbol esters, beta-PMA or beta-PDBu selectively diminish l-NE transport capacity (Vmax) with little change in NE Km [21].

Associations of SLC6A2 with chemical compounds


Physical interactions of SLC6A2


Regulatory relationships of SLC6A2


Other interactions of SLC6A2

  • In both cases, contingency table analysis revealed previously unreported gene-gene interaction between the MAOA and SLC6A2 genes (P=0.019 and 0.019, respectively) [6].
  • Support for association between ADHD and two candidate genes: NET1 and DRD1 [17].
  • Positive association between T-182C polymorphism in the norepinephrine transporter gene and susceptibility to major depressive disorder in a japanese population [32].
  • METHODS: In the present study, an analysis of interactions between the functional serotonin receptor 1A polymorphism, the norepinephrine transporter variants and the other respective polymorphisms of the above-mentioned genes is reported [33].
  • Moreover, the combination of FGF-2 and NT3, but not other neurotrophins, promotes expression or activation of one of the earliest markers expressed by presumptive sympathetic neuroblasts, the norepinephrine transporter [34].

Analytical, diagnostic and therapeutic context of SLC6A2


  1. Epidemiological evidence of an association between SLC6A2 gene polymorphism and hypertension. Ono, K., Iwanaga, Y., Mannami, T., Kokubo, Y., Tomoike, H., Komamura, K., Shioji, K., Yasui, N., Tago, N., Iwai, N. Hypertens. Res. (2003) [Pubmed]
  2. Proteomic analysis of human norepinephrine transporter complexes reveals associations with protein phosphatase 2A anchoring subunit and 14-3-3 proteins. Sung, U., Jennings, J.L., Link, A.J., Blakely, R.D. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  3. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. Shannon, J.R., Flattem, N.L., Jordan, J., Jacob, G., Black, B.K., Biaggioni, I., Blakely, R.D., Robertson, D. N. Engl. J. Med. (2000) [Pubmed]
  4. Molecular cloning and organization of the coding region of the human norepinephrine transporter gene. Pörzgen, P., Bönisch, H., Brüss, M. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  5. Pharmacogenetics and obesity: common gene variants influence weight loss response of the norepinephrine/dopamine transporter inhibitor GW320659 in obese subjects. Spraggs, C.F., Pillai, S.G., Dow, D., Douglas, C., McCarthy, L., Manasco, P.K., Stubbins, M., Roses, A.D. Pharmacogenet. Genomics (2005) [Pubmed]
  6. Gene-gene interaction between the monoamine oxidase A gene and solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 gene in anorexia nervosa (restrictive subtype). Urwin, R.E., Bennetts, B.H., Wilcken, B., Lampropoulos, B., Beumont, P.J., Russell, J.D., Tanner, S.L., Nunn, K.P. Eur. J. Hum. Genet. (2003) [Pubmed]
  7. Three-dimensional models of neurotransmitter transporters and their interactions with cocaine and S-citalopram. Ravna, A.W. World J. Biol. Psychiatry (2006) [Pubmed]
  8. Substrate binding stoichiometry and kinetics of the norepinephrine transporter. Schwartz, J.W., Novarino, G., Piston, D.W., DeFelice, L.J. J. Biol. Chem. (2005) [Pubmed]
  9. Norepinephrine transporter (NET) promoter and 5'-UTR polymorphisms: association analysis in panic disorder. Lee, Y.J., Hohoff, C., Domschke, K., Sand, P., Kuhlenbäumer, G., Schirmacher, A., Freitag, C.M., Meyer, J., Stöber, G., Franke, P., Nöthen, M.M., Fritze, J., Fimmers, R., Garritsen, H.S., Stögbauer, F., Deckert, J. Neurosci. Lett. (2005) [Pubmed]
  10. A polymorphism of the norepinephrine transporter gene in bipolar disorder and schizophrenia: lack of association. Leszczyńska-Rodziewicz, A., Czerski, P.M., Kapelski, P., Godlewski, S., Dmitrzak-Weglarz, M., Rybakowski, J., Hauser, J. Neuropsychobiology (2002) [Pubmed]
  11. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Rees, M.I., Harvey, K., Pearce, B.R., Chung, S.K., Duguid, I.C., Thomas, P., Beatty, S., Graham, G.E., Armstrong, L., Shiang, R., Abbott, K.J., Zuberi, S.M., Stephenson, J.B., Owen, M.J., Tijssen, M.A., van den Maagdenberg, A.M., Smart, T.G., Supplisson, S., Harvey, R.J. Nat. Genet. (2006) [Pubmed]
  12. Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization. Holton, K.L., Loder, M.K., Melikian, H.E. Nat. Neurosci. (2005) [Pubmed]
  13. Investigation of epistasis between the serotonin transporter and norepinephrine transporter genes in anorexia nervosa. Urwin, R.E., Bennetts, B.H., Wilcken, B., Beumont, P.J., Russell, J.D., Nunn, K.P. Neuropsychopharmacology (2003) [Pubmed]
  14. Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects. Heusser, K., Tank, J., Diedrich, A., Engeli, S., Klaua, S., Krüger, N., Strauss, A., Stoffels, G., Luft, F.C., Jordan, J. Clin. Pharmacol. Ther. (2006) [Pubmed]
  15. Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity. Spencer, T.J., Faraone, S.V., Michelson, D., Adler, L.A., Reimherr, F.W., Glatt, S.J., Biederman, J. The Journal of clinical psychiatry. (2006) [Pubmed]
  16. Increased MIBG uptake after transfer of the human norepinephrine transporter gene in rat hepatoma. Altmann, A., Kissel, M., Zitzmann, S., Kübler, W., Mahmut, M., Peschke, P., Haberkorn, U. J. Nucl. Med. (2003) [Pubmed]
  17. Support for association between ADHD and two candidate genes: NET1 and DRD1. Bobb, A.J., Addington, A.M., Sidransky, E., Gornick, M.C., Lerch, J.P., Greenstein, D.K., Clasen, L.S., Sharp, W.S., Inoff-Germain, G., Wavrant-De Vrièze, F., Arcos-Burgos, M., Straub, R.E., Hardy, J.A., Castellanos, F.X., Rapoport, J.L. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
  18. A previously undescribed intron and extensive 5' upstream sequence, but not Phox2a-mediated transactivation, are necessary for high level cell type-specific expression of the human norepinephrine transporter gene. Kim, C.H., Kim, H.S., Cubells, J.F., Kim, K.S. J. Biol. Chem. (1999) [Pubmed]
  19. Studies of the biogenic amine transporters. XI. Identification of a 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) analog that allosterically modulates the serotonin transporter. Nightingale, B., Dersch, C.M., Boos, T.L., Greiner, E., Calhoun, W.J., Jacobson, A.E., Rice, K.C., Rothman, R.B. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  20. Functional importance of the C-terminus of the human norepinephrine transporter. Distelmaier, F., Wiedemann, P., Brüss, M., Bönisch, H. J. Neurochem. (2004) [Pubmed]
  21. Acute regulation of norepinephrine transport: II. PKC-modulated surface expression of human norepinephrine transporter proteins. Apparsundaram, S., Schroeter, S., Giovanetti, E., Blakely, R.D. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  22. Transporter-mediated actions of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane. Shimazu, S., Tsunekawa, H., Yoneda, F., Katsuki, H., Akaike, A., Janowsky, A. Eur. J. Pharmacol. (2003) [Pubmed]
  23. Dopamine and norepinephrine transporter-dependent c-Fos production in vitro: relevance to neuroadaptation. Yatin, S.M., Miller, G.M., Madras, B.K. J. Neurosci. Methods (2005) [Pubmed]
  24. Functional consequences of homo- but not hetero-oligomerization between transporters for the biogenic amine neurotransmitters. Kocabas, A.M., Rudnick, G., Kilic, F. J. Neurochem. (2003) [Pubmed]
  25. Norepinephrine transporter gene variation modulates acute response to D-amphetamine. Dlugos, A., Freitag, C., Hohoff, C., McDonald, J., Cook, E.H., Deckert, J., de Wit, H. Biol. Psychiatry (2007) [Pubmed]
  26. Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type. Eshleman, A.J., Carmolli, M., Cumbay, M., Martens, C.R., Neve, K.A., Janowsky, A. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  27. Effects of long-term cigarette smoking on the human locus coeruleus. Klimek, V., Zhu, M.Y., Dilley, G., Konick, L., Overholser, J.C., Meltzer, H.Y., May, W.L., Stockmeier, C.A., Ordway, G.A. Arch. Gen. Psychiatry (2001) [Pubmed]
  28. Molecular modeling of potential new and selective PET radiotracers for the serotonin transporter. Positron Emission Tomography. Wellsow, J., Kovar, K.A., Machulla, H.J. Journal of pharmacy & pharmaceutical sciences [electronic resource] : a publication of the Canadian Society for Pharmaceutical Sciences, Société canadienne des sciences pharmaceutiques. (2002) [Pubmed]
  29. A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder. Kim, C.H., Hahn, M.K., Joung, Y., Anderson, S.L., Steele, A.H., Mazei-Robinson, M.S., Gizer, I., Teicher, M.H., Cohen, B.M., Robertson, D., Waldman, I.D., Blakely, R.D., Kim, K.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  30. Opposing functions of GDNF and NGF in the development of cholinergic and noradrenergic sympathetic neurons. Brodski, C., Schaubmar, A., Dechant, G. Mol. Cell. Neurosci. (2002) [Pubmed]
  31. Catechol-O-methyltransferase activity in CHO cells expressing norepinephrine transporter. Percy, E., Kaye, D.M., Lambert, G.W., Gruskin, S., Esler, M.D., Du, X.J. Br. J. Pharmacol. (1999) [Pubmed]
  32. Positive association between T-182C polymorphism in the norepinephrine transporter gene and susceptibility to major depressive disorder in a japanese population. Inoue, K., Itoh, K., Yoshida, K., Shimizu, T., Suzuki, T. Neuropsychobiology (2004) [Pubmed]
  33. Interaction of serotonergic and noradrenergic gene variants in panic disorder. Freitag, C.M., Domschke, K., Rothe, C., Lee, Y.J., Hohoff, C., Gutknecht, L., Sand, P., Fimmers, R., Lesch, K.P., Deckert, J. Psychiatr. Genet. (2006) [Pubmed]
  34. Growth factor synergism and antagonism in early neural crest development. Sieber-Blum, M. Biochem. Cell Biol. (1998) [Pubmed]
  35. Chromosomal mapping of the human gene for the tricyclic antidepressant-sensitive noradrenaline transporter. Brüss, M., Kunz, J., Lingen, B., Bönisch, H. Hum. Genet. (1993) [Pubmed]
  36. Norepinephrine transporter immunoblotting and radioligand binding in cocaine abusers. Mash, D.C., Ouyang, Q., Qin, Y., Pablo, J. J. Neurosci. Methods (2005) [Pubmed]
  37. A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters. Hahn, M.K., Robertson, D., Blakely, R.D. J. Neurosci. (2003) [Pubmed]
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